Cardiovascular Regulation of Blood Pressure
In human physiology, several negative feedback systems control blood pressure by adjusting heart rate, stroke volume, systemic vascular resistance and blood volume. Some allow rapid adjustment of blood pressure to cope with sudden changes such as the drop in cerebral blood pressure when rising up. Others act more slowly to provide long-term regulation of blood pressure. Even if blood pressure is steady, there may be a need to change the distribution of blood flow, which is accomplished mainly by altering the diameter of arterioles. Groups of neurons scattered within the medulla of the brain stem regulate heart rate, contractility of the ventricles, and blood vessel diameter. As a whole, this region is known as the cardiovascular center, which contains both a cardiostimulatory center and a cardioinhibitory center. The cardiovascular center includes a vasomotor center, which includes vasoconstriction and vasodilatation centers that influence blood vessel diameter. Since these clusters of neurons communicate with one another, function together, and are not clearly separated anatomically, they are usually taken as a group. The cardiovascular center receives input both from higher brain regions and from sensory receptors. Nerve impulses descend from higher brain regions including the cerebral cortex, limbic system and hypothalamus to affect the cardiovascular center. The two main types of sensory receptors that provide input to the cardiovascular center are baroreceptors and chemoreceptors. Baroreceptors are important pressure-sensitive sensory neurons that monitor stretching of the walls of blood vessels and the atria. Chemoreceptors monitor blood acidity, carbon dioxide level and oxygen level.
Output from the cardiovascular center flows along sympathetic and parasympathetic fibers of the autonomic nervous system. Sympathetic stimulation of the heart increases heart rate and contractility. Sympathetic impulses reach the heart via the cardiac accelerator nerves. Parasympathetic stimulation, conveyed along the vagus nerves, decreases heart rate. The cardiovascular center also continually sends impulses to smooth muscle in blood vessel walls via sympathetic fibers called vasomotor nerves. Thus autonomic control of the heart is the result of opposing sympathetic (stimulatory) and parasympathetic (inhibitory) influences. Autonomic control of blood vessels, on the other hand, is mediated exclusively by the sympathetic division of the autonomic nervous system.
In the smooth muscle of most small arteries and arterioles, sympathetic stimulation causes vasoconstriction and thus raises blood pressure. This is due to activation of alpha-adrenergic receptors for norepinephrine and epinephrine in the vascular smooth muscle. In skeletal muscle and the heart, the smooth muscle of blood vessels displays beta-adrenergic receptors instead, and sympathetic stimulation causes vasodilatation rather than vasoconstriction. In addition, some of the sympathetic fibers to blood vessels in skeletal muscle are cholinergic; they release acetylcholine, which causes vasodilatation.
Neural Regulation of Blood Pressure
Nerve cells capable of responding to changes in pressure or stretch are called baroreceptors. Baroreceptors in the walls of the arteries, veins, and right atrium monitor blood pressure and participate in several negative feedback systems that contribute to blood pressure control. The three most important baroreceptor negative feedback systems are the aortic reflex, carotid sinus reflex and right heart reflex.
A carotid sinus reflex is concerned with maintaining normal blood pressure in the brain and is initiated by baroreceptors in the wall of a carotid sinus. A carotid sinus is a small widening of the internal carotid artery just above the bifurcation of the common carotid artery. Any increase in blood pressure stretches the wall of the aorta and a carotid sinus, and the stretching stimulates the baroreceptors. A carotid sinus nerve, which is an afferent nerve tract that originates in carotid sinus baroreceptors, converges with the glossopharyngeal nerve, passes through the jugular foramen, reaches the rostral end of the medulla, and continues to the cardiovascular center. When an increase in aortic or carotid artery pressures is detected in this manner, the cardiovascular center responds via increased parasympathetic discharge in efferent motor fibers of the vagus nerves to the heart and by decreased sympathetic discharge in the cardiac accelerator nerves to the heart. The resulting decreases in heart rate and force of contraction lower cardiac output. In addition, the cardiovascular center sends out fewer sympathetic impulses along vasomotor fibers that normally cause vasoconstriction. The result is vasodilatation, which lowers systemic vascular resistance.
Carotid Sinus Baroreceptors
It has been demonstrated that there are two functionally different carotid sinus baroreceptors, where each type may play a different role in the regulation of blood pressure. Reference is now made to FIG. 2A, which is a plot of baroreceptor activity, measured on the ordinate as pulses or spikes per second against carotid sinus pressure on the abscissa, measured in mm Hg. Type I baroreceptors are characterized by a discontinuous hyperbolic transduction curve 10. Specifically, the electrical discharge pattern of these baroreceptors is such that, until a threshold carotid sinus pressure has been achieved, no signal is produced. However, when a carotid sinus pressure reaches the threshold, type I baroreceptor discharge commences abruptly, with an initial firing rate of about 30 spikes per second. Saturation occurs at about 200 mm Hg, at which the firing rate saturates at about 50 spikes per second. The nerve fibers connected to these types of baroreceptors are mostly thick, myelinated type A-fibers. Their conduction velocity is high, and they start firing at a relatively low threshold current (i.e., they have high impedance). The above characteristics for the type I baroreceptors suggest that they are involved in the dynamic regulation of arterial blood pressure, regulating abrupt, non-tonic changes in blood pressure.
Type II baroreceptors are pressure transducers that are characterized by a continuous transduction curve 12. Specifically, the electrical discharge pattern of these baroreceptors is such that they transmit impulses even at very low levels of arterial blood pressure. Consequently, there is no defined threshold for type II baroreceptors. The typical firing rate of type II baroreceptors in a normotensive individual is about five spikes per second. At a carotid sinus pressure of about 200 mm Hg, the firing rate saturates at about 15 spikes per second.
The nerve fibers connected to type II baroreceptors are either thin, myelinated type A fibers, or unmyelinated type C fibers. Their conduction velocity is low and, when stimulated experimentally, they start firing at a relatively high threshold current, due to their relatively low impedance. The above characteristics of type II baroreceptors suggest that they are involved in the tonic regulation of arterial blood pressure, and that they play a role in the establishment of baseline blood pressure (i.e., diastolic blood pressure).
Modulation of Baroreceptor Activity
The baroreceptive endings of a carotid sinus nerve and the aortic depressor nerve are the peripheral terminals of a group of sensory neurons with their soma located in the petrosal and nodose ganglia. The endings terminate primarily in the tunica adventitia of a carotid sinus and aortic arch. When stretched, they depolarize. Action potentials are consequently triggered from a spike-initiating zone on the axon near the terminal. The action potentials travel centrally to the nucleus tractus solitarius in the medulla. There, the sensory neurons synapse with a second group of central neurons, which in turn transmit impulses to a third group of efferent neurons that control the parasympathetic and sympathetic effectors of the cardiovascular system. The vascular structure of a carotid sinus and aortic arch determines the deformation and strain of the baroreceptor endings during changes in arterial pressure. For this reason, structural changes in the large arteries and decreased vascular distensibility, also known as compliance, are often considered the predominant mechanisms responsible for decreased baroreflex sensitivity and resetting of baroreceptors, which occur in hypertension, atherosclerosis, and aging.
The process of mechanoelectrical transduction in the baroreceptors depends on two components: (1) a mechanical component, which is determined by the viscoelastic characteristics of coupling elements between the vessel wall and the nerve endings, and (2) a functional component, which is related to (a) ionic factors resulting from activation of channels or pumps in the neuronal membrane of the baroreceptor region, which alter current flow and cause depolarization resulting in the generation of action potentials, and (b) paracrine factors released from tissues and cells in proximity to the nerve endings during physiological or pathological states. These cells include endothelial cells, vascular muscle cells, monocytes, macrophages, and platelets. The paracrine factors include prostacyclin, nitric oxide, oxygen radicals, endothelin, platelet-derived factors, and other yet unknown compounds. Extensive animal studies conducted in the 1990s support the concept that the mechanoelectrical transduction in baroreceptor neurons occurs through stretch-activated ionic channels, whose transduction properties are affected by the aforementioned factors.
There exists evidence indicating a dependency of the baroreflex on the temporal characteristics of discharges in the cardiovascular afferent fibers. The coupling of afferent baroreceptor activity with the central group of neurons leads to inhibition of sympathetic nerve activity. This coupling was examined by determining the relationship between afferent baroreceptor activity and efferent sympathetic nerve activity measured simultaneously.
Sustained inhibition of sympathetic nerve activity is not simply a function of baroreceptor spike frequency, but depends on the phasic burst pattern, with on and off periods during systole and diastole, respectively. Sympathetic nerve activity is disinhibited, because of what may be viewed as a “central adaptation,” during nonpulsatile, nonphasic baroreceptor activity. It is not actually the pulse pressure that is important in sustaining sympathetic inhibition, but rather the magnitude of pulsatile distension of a carotid sinus and the corresponding phasic baroreceptor discharge. One would predict that a decrease in large artery compliance, as might occur in chronic hypertension or atherosclerosis, could result in a decrease in pulsatile distension of a carotid sinus and a blunting of the phasicity of baroreceptor input. There is progressive loss of the buffering capacity of the baroreflex because of central adaptation. It has been shown experimentally that the reflex inhibition of sympathetic nerve activity is most pronounced at lower frequencies of pulsatile pressure and during bursts of baroreceptor activity (between 1 and 2 Hz). When the burst or pulse frequency exceeded 3 Hz, there is known to be a significant disinhibition of sympathetic nerve activity, despite a maintained high level of total baroreceptor spike frequency per unit time. Thus, at very rapid pulse rates the efficiency of afferent-efferent coupling is reduced.
In a study conducted using young (1 year old) and old (10 years old) beagle dogs, it was found that the reflex inhibition of sympathetic nerve activity after a rise in carotid sinus pressure was maintained in the young but was very transient in the old dogs. The “escape” of sympathetic nerve activity from baroreflex inhibition occurred in the old dogs despite a maintained increase in afferent baroreceptor activity. Thus, the major defect in the baroreflex with aging may not be a structural vascular defect or an impaired baroreceptive process, but rather a central neural defect in the afferent-efferent coupling. It is proposed in U.S. Pat. No. 4,201,219 to employ a neurodetector device in order to generate pulsed electrical signals. The frequency of the impulses is utilized to pace the heart directly in order to modify the cardiac rate. This approach has not been generally accepted, as there were serious technical difficulties with the implantation, and the reliability of the apparatus. In U.S. Pat. No. 3,650,277 it is proposed to treat hypertension by stimulating afferent nerve paths from the baroreceptors of a patient, in particular the nerves from a carotid sinus. Short electrical pulses are used during a limited period of the cardiac cycle. It is necessary to synchronize an electrical signal generator to the heart activity of the patient, either by measuring electrical activity of the heart, or by using a transducer that is capable of measuring instantaneous blood pressure.
Another attempt at simulating the baroreceptor reflex is disclosed in U.S. Pat. No. 4,791,931, wherein a pressure transducer and a cardiac pacemaker are implanted. The pacing rate is variable and is responsive to arterial pressure.
Peripheral Chemoreceptors and Central Chemoreceptors
The primarily function of chemoreceptors is to regulate respiratory activity. This is an important mechanism for maintaining arterial blood pO2, pCO2, and pH within appropriate physiological ranges. For example, a fall in arterial pO2 (hypoxemia) or an increase in arterial pCO2 (hypercapnia) leads to an increase in the rate and depth of respiration through activation of the chemoreceptor reflex. Chemoreceptor activity, however, also affects cardiovascular function either directly (by interacting with medullary vasomotor centers) or indirectly (via altered pulmonary stretch receptor activity). Respiratory arrest and circulatory shock (these conditions decrease arterial pO2 and pH, and increase arterial pCO2) dramatically increase chemoreceptor activity leading to enhanced sympathetic outflow to the heart and vasculature via activation of the vasomotor center in the medulla. Cerebral ischemia activates central chemoreceptors, which produces simultaneous activation of sympathetic and vagal nerves to the cardiovascular system.
Carotid bodies are located on the external carotid arteries near their bifurcation with the internal carotids. Each carotid body is a few millimeters in size and has the distinction of having the highest blood flow per tissue weight of any organ in the body. Afferent nerve fibers join with the sinus nerve before entering the glossopharyngeal nerve. A decrease in carotid body blood flow results in cellular hypoxia, hypercapnia, and decreased pH that lead to an increase in receptor firing. The threshold pO2 for activation is about 80 mmHg (normal arterial pO2 is about 95 mmHg). Any elevation of pCO2 above a normal value of 40 mmHg, or a decrease in pH below 7.4 causes receptor firing. If respiratory activity is not allowed to change during chemoreceptor stimulation (thus removing the influence of lung mechanoreceptors), then chemoreceptor activation causes bradycardia and coronary vasodilation (both via vagal activation) and systemic vasoconstriction (via sympathetic activation). If respiratory activity increases, then sympathetic activity stimulates both the heart and vasculature to increase arterial pressure.
It is an object of the present invention to provide an improved method for treating cerebrovascular conditions, particularly ischemic events in the brain, by stimulating a carotid baroreceptor and/or chemoreceptor, thereby reducing carebrovascular tone, leading to increased cerebral blood flow (CBF) and potentially improved viability of metabolically compromised brain tissue.
It is another object of the invention to provide a simple-to-use endovascular system for electrically stimulating the nerves of carotid baroreceptors and/or chemoreceptors.
It is yet another object of the invention to provide a method to overcome tachyphylaxis of the CBF by alternating between stimulation of carotid chemoreceptor and carotid baroreceptor, and by alternating between baroreceptors and/or chemoreceptors on two sides of the body.
It is still other object of the invention to provide a method to reversibly and safely position (or anchor) an endovascular system for electrically engaging a carotid chemoreceptor and/or baroreceptor.
It is further an object of the invention to provide an improved method for treating ischemic events in the brain of a living body by estimating cerebral blood flow while stimulating either a carotid baroreceptor or carotid chemoreceptor, and adapting parameters of stimulation so as to optimize the response of the cerebral vascular bed to the stimulation